{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:06:23Z","timestamp":1778569583971,"version":"3.51.4"},"reference-count":63,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T00:00:00Z","timestamp":1767830400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union-NextGenerationEU","award":["BG-RRP-2.004-0004-C01"],"award-info":[{"award-number":["BG-RRP-2.004-0004-C01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: The anterior cruciate ligament (ACL) and medial collateral ligament (MCL) display strikingly different healing behaviors, despite their similar structural roles within the knee. The epiligament (EL)\u2014a vascular and cellular envelope surrounding each ligament\u2014has emerged as a critical determinant of repair capacity. The aim of this study was to perform a region-specific, comparative analysis of EL molecular profiles in the ACL and MCL to elucidate the mechanisms underlying their contrasting reparative outcomes. Methods: Human ACL and MCL specimens were obtained from 12 fresh knee joints. Immunohistochemical labeling for CD34, \u03b1-smooth muscle actin (\u03b1-SMA), and vascular endothelial growth factor (VEGF) was performed across proximal, mid-substance, and distal EL regions. Quantitative image analysis using IHC Profiler for ImageJ generated semiquantitative (negative, low-positive, positive) distributions, and inter-ligament comparisons were quantified using t-tests (p\u2009 &lt; \u20090.05). Results: Distinct, region-specific EL signatures were identified. The ACL EL exhibited strong proximal \u03b1-SMA expression (0% neg\/66.8% low+\/33.2%+) and notable distal CD34 positivity (0% neg\/83.3% low+\/16.7%+), while VEGF expression was confined to the mid-substance (\u224855% low+\/26%+). In contrast, the MCL EL was largely negative for CD34 and VEGF across all regions, showing a homogeneous but functionally oriented \u03b1-SMA profile: proximally negative, sparse mid positivity, and high distal low-positive staining (93.4% low+). Differences in proximal and distal CD34 and \u03b1-SMA expression between the ACL and MCL were highly significant (p\u2009 &lt; \u20090.0001\u20130.001), confirming a mechanistic divergence in EL organization. Conclusions: The ACL EL is regionally heterogeneous, vascularly biased, and enriched in contractile \u03b1-SMA+ cells, suggesting localized but poorly coordinated reparative potential. In contrast, the MCL EL is structurally uniform, with distributed \u03b1-SMA activity supporting stable wound contraction and tissue continuity, despite limited angiogenic signaling. These findings indicate that the ACL\u2019s failure to heal is not attributable to the absence of progenitor or angiogenic factors, but rather to its fragmented spatial organization and dominant contractile phenotype. Therapeutically, preserving and modulating the EL, particularly its CD34+ and \u03b1-SMA+ compartments, could be key to enhancing intrinsic ACL repair and improving outcomes in ligament reconstruction and regeneration.<\/jats:p>","DOI":"10.3390\/jcm15020510","type":"journal-article","created":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T11:11:21Z","timestamp":1767870681000},"page":"510","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Can the Spatial Heterogeneity in the Epiligament Explain the Differential Healing Capacities of the ACL and MCL?"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4774-6507","authenticated-orcid":false,"given":"Lyubomir","family":"Gaydarski","sequence":"first","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boycho","family":"Landzhov","sequence":"additional","affiliation":[{"name":"Department of Anatomy, Histology and Embryology, Medical University of Sofia, 1431 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard Shane","family":"Tubbs","sequence":"additional","affiliation":[{"name":"Department of Anatomical Sciences, St. George\u2019s University, St. George 1473, Grenada"},{"name":"Department of Neurosurgery, Tulane University School of Medicine, New Orleans, LA 70112, USA"},{"name":"Department of Neurology, Tulane University School of Medicine, New Orleans, LA 70112, USA"},{"name":"Department of Structural and Cellular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA"},{"name":"Department of Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8343-0337","authenticated-orcid":false,"given":"Georgi P.","family":"Georgiev","sequence":"additional","affiliation":[{"name":"Department of Orthopedics and Traumatology, University Hospital Queen Giovanna-ISUL, Medical University of Sofia, 1527 Sofia, Bulgaria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,8]]},"reference":[{"key":"ref_1","first-page":"299","article-title":"Clinical management of ligament injuries of the knee and postoperative rehabilitation","volume":"Volume 21","author":"Oliveira","year":"2017","journal-title":"Regenerative Strategies for the Treatment of Knee Joint Disabilities"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Rowbotham, E., and Grainger, A.J. 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